Project Summary/Abstract Despite multiple clinical trials testing medications targeting dopaminergic, serotonergic, cholinergic, and gaba-ergic systems, no effective medication for methamphetamine (MA) use disorder is currently available. Studies of medications with novel targets and mechanisms are needed. The prefrontal cortex- nucleus accumbens glutamatergic circuit plays an important role in the persistent risk of relapse in psychostimulant addiction and preclinical studies suggest that targeting metabotropic glutamate receptors (mGluR) 2/3 may be effective in counteracting MA-induced glutamatergic adaptations, thereby preventing relapse. Pomaglumetad methionil (LY2140023, POMA) is an orally available prodrug of LY404039, a selective mGluR 2/3 agonist, in clinical development for schizophrenia by Denovo Biopharma. POMA was well tolerated in multiple phase 2/3 clinical trials with minimal psychiatric or cardiovascular adverse events and the excellent safety and tolerability profile of POMA suggests that POMA is an excellent candidate for clinical development as an mGluR 2/3 agonist to prevent MA relapse. As a result, UCLA and Denovo have formed a strategic alliance aimed at the clinical development of POMA for MA use disorder. The current proposal will leverage NIDA funds to complete the necessary phase 1 safety-interaction study needed to kick-start subsequent clinical development of POMA for MA use disorder. The proposed study is an inpatient phase I safety-interaction trial of POMA in participants with MA use disorder to provide the initial safety, tolerability, and pharmacokinetic (PK) data required by the FDA to advance POMA to phase 2 safety and efficacy testing. In addition, the study will investigate potential effects of POMA on a laboratory self-administration model of MA relapse. The design is a randomized, double- blind, placebo-controlled multiple ascending-dose study in 24 (with goal of at least 8 female) non-treatment seeking participants with MA use disorder. Three cohorts of 8 participants each will be randomized within each cohort to receive POMA (N = 6) or placebo (N = 2) in a 6:2 ratio while undergoing intravenous (IV) MA infusions and assessments of cardiovascular response, MA subjective effects, adverse events, PK, and MA self-administration. The POMA dose will be 40 mg twice daily (BID) in cohort 1, 80 mg BID in cohort 2, and 160 mg BID in cohort 3. The study will address the following specific aims: (1) to determine the safety and tolerability of POMA with IV MA as assessed via cardiovascular response, MA subjective effects, and adverse events, (2) to determine whether co-administration of POMA and MA alters the pharmacokinetics of MA and/or POMA, and (3) to determine whether treatment with POMA alters MA self-administration in a model of MA relapse. Criteria for advancement of POMA to a phase 2 efficacy trial are the absence of a clinically significant effect of POMA on MA cardiovascular response, subjective effects, adverse events (Aim 1) or PK (Aim 2). Potential effects of POMA on the self-administration model of MA relapse (Aim 3) will be used to determine whether to employ a relapse prevention design for the subsequent phase 2 efficacy trial.